Methysergide has superior efficacy for migraine prophylaxis and has been available commercially as oral tablets (i.e., Sansert® or Deseril®) for the treatment and/or prevention of migraine headaches. Since methysergide is a 5HT2B antagonist, it should not have undesirable side effects such as cardiac and non-cardiac fibrosis, including cardiac valvulopathy. However, methysergide has low oral bioavailability and is metabolized in-vivo to the metabolite methylergotmetrine, which is a 5HT2B agonist, and consequently leads to development of fibrosis (e.g., retroperitoneal fibrosis, pleuropulmonary fibrosis, subendocardial fibrosis and fibrotic thickening of cardiac valves) in many patients who use Sansert® or Deseril® for extended therapy.
Accordingly, there is a continuing need for novel methysergide derivatives which have 5HT2B antagonist activity, superior bioavailability and are not metabolized in vivo into a 5HT2B agonist.